Abiraterone acetate, chemically designated as (3β)-17-(3-pyridinyl)-androsta-5,16-dien-3-yl acetate of formula
is a prodrug which is converted in vivo to abiraterone, 17-(3-pyridyl)-androsta-5,16-dien-3β-ol.
Abiraterone is a potent inhibitor of human cytochrome P45017α, a potential target enzyme in the treatment of hormone-dependent prostatic carcinoma.
Abiraterone acetate is the active ingredient of the approved drug (Zytiga®) which is administered in a solid oral dosage form (250 mg tablet).
Zytiga® in combination with prednisone is indicated for the treatment of patients with metastatic castration resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.
Literature reports several processes for the preparation of abiraterone or derivatives thereof.
Synthetic approaches to abiraterone generally start from a dehydroepiandrosterone-3-acetate substrate.
Abiraterone was first described in patent application EP 0633893 (BTG International Ltd.) covering 16,17-ene-17-(3-pyridyl) steroids as a class of compounds useful in the treatment of androgen- and oestrogen-dependent disorders. EP' 893 reports two synthetic routes which comprise replacing a 17-oxo ketone residue in its enol form by a leaving group in a Palladium complex-catalysed cross-coupling reaction with a pyridyl ring-substituted boron compound. Said replacement can be via steroidal enol triflate or a halo derivative. Particularly, in the specific experimental work, abiraterone acetate is prepared from dehydroepiandrosterone-3-acetate substrate via triflating in the presence of 2,6-di-t-butyl-4-methylpyridine; the triflate intermediate is purified by column chromatography to separate the unreacted and the triene impurity and then isolated from hexane. The pyridine moiety was inserted in the steroid nuclea by a palladium catalysed cross-coupling of the enol triflate derivative by using diethyl-(3-pyridyl)-borane in aqueous THF with sodium carbonate as nucleophilic activator. Chromatography, again, is required to give the desired compound. However, it has been observed that the overall yield of the process is low (around 48%) and chromatography appears to be the only tool able to provide a substantially pure product which is then crystallised from apolar solvents and, optionally, used in the downstream of the process.
EP 0721461 (BTG International Ltd.) describes an improved method for the preparation of (3β)-acyloxy-16,17-ene-17-(3-pyridyl) steroids; especially, the preferred compound (3β)-acetoxy-17-(3-pyridyl)-androsta-5,16-diene is prepared via a vinyl iodide intermediate by using the unprotected (3β)-hydroxy compounds as substrate. The application reports that triflates are expensive starting materials and so an alternative route is desirable; in addition, the triflating reaction has to be carried out on the 3-acetate as protecting group, said 3-acetate being, then, hydrolysed to the 3-ol in a separate step. However, the estimated overall yield starting from dehydroepiandrosterone is low (around 41%) and, mainly, a final purification by reverse phase chromatography is required.
WO 2006/021776 (BTG International Ltd.) describes novel salt forms of C2-C4 acyl esters of abiraterone or a derivative thereof and to a process for the preparation of abiraterone or a salt or derivative thereof. The application provides for an alternative method whereby a salt of the desired compound is recovered from a suitable solvent; operatively, the product of the triflate reaction is used in the Suzuki coupling unpurified. Salt isolation is meant to eliminate undesired by-product (triene) as well as unreacted starting material which remain in solution so as to simplify the purification process; expensive and time-consuming chromatography steps are to be avoided. The preferred salt is abiraterone acetate methanesulfonate which is, preferably, recovered from methyl tert-butyl ether.
WO 2006/021777 (BTG International Ltd.) describes a process for the preparation of abiraterone or C2-C4 acyl esters of abiraterone or a derivative thereof which comprises a triflating step by which a ketone of formula (II) is converted into a triflate of formula (III):
wherein R′ is hydrogen or a lower acyl group having 2 to 4 carbon atoms; the triflating step being conducted in the presence of a base comprising a tertiary or heterocyclic amine such that the pKa of the conjugate acid at 25° C. is within the range 5.21 to 12. The application reports that known prior art recommend the use of 2,6-di-tert-butyl-4-methylpyridine in the triflating step since simple bases can lead to the formation of undesirable by-product. Particularly, the inventors observed that by using specific 2,6-di-tert-butyl-4-methylpyridine when triflating lower acyl protected substrate, elimination of the acid occurred giving an undesired triene by-product of formula

Subsequent coupling as well as isolation steps to abiraterone acetate are carried out by following the teachings of the International application WO '776 above. However, the estimated overall yield of the process starting from dehydroepiandrosterone 3-acetate is very low (around 32%) with a purity around 97%; isolation as, inter alia, mesylate salt entails an additional neutralization and optionally crystallization step(s) with further loss in yield.
Furthermore, Chinese application CN 101768199 discloses abiraterone acetate polymorphs A, B, C and D; methods of preparing said polymorphs comprise recrystallizing abiraterone acetate which is separated and purified by a chromatographic column in different solvents.